Our objective is to identify the neural substrates and mechanisms that mediate the neural control of the immune system. The proposed neuroimmune model states that the immune system signals the brain and the CNS subsequently modifies peripheral immune function. We showed that an immune challenge activates central autonomic regulatory regions, increases sympathetic output to the spleen, and modifies splenic immune function via the sympathetic splenic nerve. Similarly, stress activates the neural-immune regulatory circuit and also suppresses splenic macrophage function via the splenic nerve. We propose that immune signals and stress modify CNS activity via a specific signal transduction cascade and activation of this cascade alters autonomic and endocrine regulatory circuits which then signal the immune system via definable pathways and chemical mediators. HIV-1 may disrupt this neural- immune regulatory circuit and we hypothesize it produces autonomic dysregulation and disarms the neural regulation of the immune system. Our aim is to identify the neuroanatomical and neurochemical mechanisms mediating the effects of endotoxin, stress, and the HIV-1 viral coat protein gp120 on splenic macrophage function. Central induction of c-fos protein and multiunit electrical activity in the brain will index activation of the central circuit by immune stimuli and nerve recordings will measure sympathic output to the spleen. In vivo splenic macrophage cytokine production following an endotoxin challenge will measure immune function and corticosterone levels will index endocrine activation. Intracranial injections of gp120, prostaglandins, neuropeptide and nitric oxide agonist and antagonist or stress will be combined with an endotoxin challenge to establish the organization of the signalling cascade and to determine if it is a target for gp120. Finally, simultaneous brain and splenic nerve recordings will monitor the activation and output of the regulatory system following systemic and central injections and provide a direct link between the central activation of the neural-immune axis and alterations in splenic macrophage function. These experiments will characterize the functional pathways from the brain to the spleen and determine the effects of gp120 on this regulatory system.